Transcription elongation by RNA polymerases (RNAPs) is functionally connected with DNA replication, repair, and chromatin organization, and thus affects the overall integrity and organization of the genome. Taken together with the central role of the post-initiation events in regulation of mRNA synthesis, the complexity of the network involving RNAP suggests that the changes in the transcription elongation rate, fidelity and the propensity of RNAP to undergo transcription arrest has a broad impact on cell physiology. The analyses of the biological role of transcription fidelity will promote our understanding of RNAP substrate specificity. It will provide additional insights into the mechanisms and side effects of the clinically relevant NTP analogues. In addition, transcription fidelity might be connected to the transcription-coupled DNA repair. Specifically, we have recently established that the ability of yeast/mammalian Pol II to recognize the lesion in the DNA is determined by the mechanisms similar to those regulating cognate NTP substrate selection. The scope of the research may be expanded to address the interconnection of transcription elongation and other DNA transactions.